tbuckley/cabot-search huggingface dataset:
Phase 1b study of bavdegalutamide, an androgen receptor PROTACdegrader, combined with abiraterone in patients with metastatic prostate cancer.
Authors: Neal D. Shore, John Shen, Michael Edward Devitt, Haolan Lu, Jeanette Alicea, Janaki Parameswaran, Deborah Chirnomas, Xin Gao, Meredith McKean
Journal: Journal of Clinical Oncology (2022)

TPS5106 Background: Bavdegalutamide (ARV-110) is a novel, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that targets wild-type androgen receptor (AR) and clinically relevant mutants. Bavdegalutamide demonstrated tumor growth inhibition in multiple xenograft models (eg, AR gene amplification, AR mutation, enzalutamide resistance, and enzalutamide insensitivity). In a phase 1/2 study (NCT03888612), bavdegalutamide showed clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received 1–2 prior novel hormonal agents (eg, abiraterone and/or enzalutamide), including heavily pretreated patients. Abiraterone is approved, in combination with a corticosteroid, to treat patients with mCRPC or with high-risk castration-sensitive prostate cancer (CSPC). Up to a third of patients treated with abiraterone develop primary resistance to this drug and nearly all patients experience disease progression. Here we describe a phase 1b study that will evaluate the combination of bavdegalutamide with abiraterone at the initiation of progression on abiraterone (prostate-specific antigen [PSA] progression without radiographic progression) to test if the addition of bavdegalutamide will overcome resistance to abiraterone and re-establish the AR pathway blockade in patients with prostate cancer. Methods: Eligible patients are men ≥18 years of age with histologically, pathologically, or cytologically confirmed adenocarcinoma of the prostate and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients must be receiving ongoing treatment with stable doses of abiraterone and a concomitant corticosteroid for mCRPC or CSPC and have PSA progression ≥16 weeks after initiation of abiraterone, ≥2 rising PSA values measured ≥1 week apart, and no radiographic evidence of disease progression while receiving abiraterone. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analogue or inhibitor or orchiectomy is required. Prior treatment with enzalutamide, apalutamide, darolutamide, or experimental AR-directed therapies is not permitted. Bavdegalutamide, abiraterone, and a corticosteroid will be administered daily in 28-day cycles. Primary objectives are to evaluate the safety and tolerability of bavdegalutamide plus abiraterone and determine the recommended phase 2 dose and schedule of this combination (based on the incidence of first-cycle dose-limiting toxicities and the frequency and severity of adverse events and laboratory abnormalities). Clinical trial information: NCT05177042.
Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations
Authors: Linea N. Toksvang, Shawn H. R. Lee, Jun J. Yang, Kjeld Schmiegelow
Journal: Leukemia (2022)

Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone-that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.
Transperineal interstitial Laser Ablation (TPLA) of the prostate for selected patients with benign prostatic obstruction: Step-by-step technique and preliminary findings
Authors: C. Bisegna, F. Sessa, R. Campi, A. Rivetti, M.L. Gallo, P. Barzaghi, G. Vittori, A. Tuccio, P. Polverino, P. Spatafora, A. Minervini, M. Carini, S. Serni
Journal: European Urology (2022)
SAF-189s in advanced, ALK-positive, non–small cell lung cancer: Results from a first-in-human phase 1/2, multicenter study.
Authors: Jin-Ji Yang, Jianying Zhou, Ying Cheng, Mingjun Li, Qiong Zhao, Zhiye Zhang, Aimin Zang, Yun Fan, Ai-Min Hui, Yongchu Zhou, Zhuli Wu, Juan Sun, Zhaoyang Pan, Jingjun Qiu, Yi-Long Wu
Journal: Journal of Clinical Oncology (2022)

9076 Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]
Political environment and mortality rates in the United States, 2001-19: population based cross sectional analysis
Authors: Haider J Warraich, Pankaj Kumar, Khurram Nasir, Karen E Joynt Maddox, Rishi K Wadhera
Journal: BMJ (2022)

To assess recent trends in age adjusted mortality rates (AAMRs) in the United States based on county level presidential voting patterns.Cross sectional study.USA, 2001-19.99.8% of the US population.AAMR per 100 000 population and average annual percentage change (APC).The Centers for Disease Control and Prevention WONDER database was linked to county level data on US presidential elections. County political environment was classified as either Democratic or Republican for the four years that followed a November presidential election. Additional sensitivity analyses analyzed AAMR trends for counties that voted only for one party throughout the study, and county level gubernatorial election results and state level AAMR trends. Joinpoint analysis was used to assess for an inflection point in APC trends.The study period covered five presidential elections from 2000 to 2019. From 2001 to 2019, the AAMR per 100 000 population decreased by 22% in Democratic counties, from 850.3 to 664.0 (average APC -1.4%, 95% confidence interval -1.5% to -1.2%), but by only 11% in Republican counties, from 867.0 to 771.1 (average APC -0.7%, -0.9% to -0.5%). The gap in AAMR between Democratic and Republican counties therefore widened from 16.7 (95% confidence interval 16.6 to 16.8) to 107.1 (106.5 to 107.7). Statistically significant inflection points in APC occurred for Democratic counties between periods 2001-09 (APC -2.1%, -2.3% to -1.9%) and 2009-19 (APC -0.8%, -1.0% to -0.6%). For Republican counties between 2001 and 2008 the APC was -1.4% (-1.8% to -1.0%), slowing to near zero between 2008 and 2019 (APC -0.2%, -0.4% to 0.0%). Male and female residents of Democratic counties experienced both lower AAMR and twice the relative decrease in AAMR than did those in Republican counties. Black Americans experienced largely similar improvement in AAMR in both Democratic and Republican counties. However, the AAMR gap between white residents in Democratic versus Republican counties increased fourfold, from 24.7 (95% confidence interval 24.6 to 24.8) to 101.3 (101.0 to 101.6). Rural Republican counties experienced the highest AAMR and the least improvement. All trends were similar when comparing counties that did not switch political environment throughout the period and when gubernatorial election results were used. The greatest contributors to the widening AAMR gap between Republican and Democratic counties were heart disease (difference in AAMRs 27.6), cancer (17.3), and chronic lower respiratory tract diseases (8.3), followed by unintentional injuries (3.3) and suicide (3.0).The mortality gap in Republican voting counties compared with Democratic voting counties has grown over time, especially for white populations, and that gap began to widen after 2008.
Molecular characterization of NF1-mutated NSCLC and clinical outcomes.
Authors: Christopher Gates, Konstantinos Sdrimas, Andrew Elliott, Hossein Borghaei, Joanne Xiu, Phillip Walker, Ari M. Vanderwalde, Stephen V. Liu, Jean Gabriel Bustamante Alvarez
Journal: Journal of Clinical Oncology (2022)

9086 Background: NF1 is a tumor suppressor gene that regulates the RAS-MAPK and mTOR pathways. Co-mutations previously observed with NF1-mutations (mt) include TP53, KRAS, EGFR and rarely HER2, STK11, and PIK3CA mutations. We report a comprehensive molecular characterization with clinical outcomes analyses for NF1-mt non-small cell lung cancer (NSCLC). Methods: Next-generation sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome) was performed for NSCLC patient (pt) samples (n = 10,310) submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ).. RAS-MAPK and PI3K-AKT-MTOR signaling were assessed by transcriptional signatures of pathway activation (MAPK pathway Activation Score [MPAS], Wagle, 2018; and GSEA Hallmarks collection, respectively)., PD-L1 by immunohistochemistry (IHC, positive: TPS ≥1%), high tumor mutational burden (TMB) defined as ≥10 mut/Mb, and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High) was assessed by IHC/NGS. Overall survival (OS) was obtained from insurance claims. Statistical significance was determined using Chi-square &amp; Wilcoxon rank sum tests. P-value adjust for multiple hypothesis testing (Benjamini-Hochberg). Results: NF1-mt were identified in 1,045 NSCLC samples (10.1%). Concurrent KRAS, EGFR, ERBB2, BRAF or MET alterations are noted in Table 1, with no ROS1, RET or ALK fusions identified. Compared to NF1-wt, NF1-mt NSCLC was associated with increased RAS-MAPK expression (3.0-fold, P &lt; 0.0001), while PI3K-AKT-MTOR-signaling was not significantly increased (2.1-fold, P = 0.12). Rates of TMB-High (51.7% vs 32.5%, P &lt; 0.0001), PD-L1+ (69.1% vs 58.8%, P = 0.06), and dMMR/MSI-High (1.7 vs 0.7%, P &lt; 0.05) were higher in NF1-mt samples. OS and duration on treatment from the start of Pembrolizumab (HR: 1.0 and 1.0, respectively) or other IOs (HR: 0.9 and 1.0, respectively) were not significantly different between NF1-mt and NF1-wt patients, However, among NF1-mt samples, high TMB and TP53-wt were associated with better OS (HR 0.6, P &lt; 0.05 each). Conclusions: NF1-mt patients rarely harbored actionable NSCLC driver co-alterations. NF1-mt cases showed increased activation of RAS-MAPK axis, which may represent a potential pathway to target with MEK inhibitors. NF1- mt are responsive to immunotherapy and better outcomes are seen with high TMB and absence of TP53 mutations. Further work is warranted to determine the influence of actionable drivers on targeted therapy outcomes in NF1-mt NSCLC. [Table: see text]
Efficacy and safety of low-dose radiotherapy (LDRT) concurrent atezolizumab plus chemotherapy as first-line therapy for ES-SCLC : Interim analysis of Phase II MATCH trial.
Authors: Lin Zhou, Jianguo Sun, Conghua Xie, Youling Gong, Meijuan Huang, Zhiyong Yuan, Lin Wu, Hui Wang, Nan Bi, Xu Yaping, Jiang Zhu, Yan Zhang, Min Fan, Bingwen Zou, Min Yu, Feifei Na, Weigang Xiu, Xuanwei Zhang, Jianxin Xue, You Lu
Journal: Journal of Clinical Oncology (2022)

e20611 Background: The IMpower 133 trial represents the current SoC in the 1L setting for pts with ES-SCLC but still needs further efficacy improvement such as objective response rate (ORR, ̃60% in both arms) which may lead to survival benefit. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. We have reported that LDRT plus ICIs in pretreated ES-SCLC was well tolerated with an improved efficacy. Here we conducted MATCH study to investigate the clinical benefits of adding LDRT to Atezo plus chemotherapy in ES-SCLC pts as 1L therapy. Methods: The MATCH study was a single-arm phase II trial conducted in eight centers across China. A Simon’s minimax two-stage design was adopted. Pts with measurable disease per RECIST v1.1 at baseline with ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was ORR confirmed by investigators after two consecutive evaluations ≥ 4 weeks apart. The secondary endpoints included disease control rate (DCR) and safety. Results: This is the report on the completed 1st phase of the trial. By the cutoff date of 26 th August 2021, of the first 21 evaluable pts, 20 were males; mean age was 60.2 y and 85.7% pts had ECOG PS of 1. Previous smokers were 85.7%. Most pts were staged T4 (n = 15, 71.4%), N3 (n = 18, 85,7%) and M1(n = 17, 81.0%). The most common sites of metastasis were bone (47.1%) and liver (11.8%). Median follow-up was 4.0 m (range: 2.6-8.0 m). The confirmed ORR was 95.2% (95% CI, 76.2%-99.9%), among whom all pts were PR. DCR was 100%. The safety profile was consistent with the previous reports. Neutrophil count decreased (66.7%), white blood cell count decreased (42.9%) and anaemia (38.1%) were the most common grade 3-4 adverse events. No grade 5 AE occurred. Two pts experienced AEs leading to treatment withdrawal. IrAEs by preferred term were reported in 3(14.3%) pts: 2 were immune-mediated hyperthyroidism (grade 2) and 1 was immune-mediated enterocolitis (grade 3). No radiation pneumonitis occurred. Conclusions: The study met the response criteria for 1st phase. The combination of LDRT and Atezo plus chemotherapy showed promising benefit and was tolerable in pts with ES-SCLC. The 2nd phase is ongoing. Clinical trial information: NCT04622228.
The resurgence of wild poliovirus in Pakistan and Afghanistan: A new setback for polio eradication
Authors: Muhammad Suleman Rana, Rana Jawad Asghar, Muhammad Usman, Aamer Ikram, Muhammad Salman, Massab Umair, Syed Sohail Zahoor Zaidi, Muhammad Anas, Nadeem Ullah
Journal: Journal of Infection (2022)
Timing of onset of systemic treatment in asymptomatic patients with metastatic pancreatic cancer: An international expert survey and case-vignette study.
Authors: Simone Augustinus, Hanneke W.M. Van Laarhoven, Geert A. Cirkel, Jan Willem de Groot, Bas Groot Koerkamp, Teresa Macarulla, Davide Melisi, Eileen Mary O'Reilly, Hjalmar van Santvoort, Tara Mackay, Marc G Besselink, Johanna Wilmink
Journal: Journal of Clinical Oncology (2022)

e16256 Background: The number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC) is increasing, mostly due to increased use of imaging. Traditionally, systemic therapy is started immediately on disease detection. However, one perspective is that delaying therapy may preserve/maintain quality of life for longer. The impact on survival is unknown. The aim of this study was to gain further insights into current perspectives and clinical decision making regarding timing of start of systemic treatment in asymptomatic patients with mPDAC. Methods: An online survey (11 questions and 9 case vignettes) was sent to all first and last authors of published clinical trials on mPDAC over the past 10 years and medical oncologists of the Dutch Pancreatic Cancer Group. Differences in preferred treatment (i.e. immediate vs. delayed) between continents and years of experience (i.e. &lt; 5 years, 5-10 years, &gt; 11 years) were analyzed using the Fisher’s exact test. Results: Seventy-eight of 291 (27%) medical oncologists responded from 15 countries over 4 continents (62% Europe, 23% North America, 10% Asia, and 5% Australia). Most respondents worked in an academic hospital (73%) and reported more than 11 years’ experience (76%). The majority (63%) preferred immediate start of chemotherapy after diagnosis of metastastic disease. Thirty-two percent favored delayed treatment; 5% at symptom occurrence, 5% at objective disease progression, and 22% either at symptom occurrence or objective disease progression (whichever comes first). For the case vignettes, immediate treatment was preferred in 6/9 cases (67%). In the 3 remaining cases, delayed treatment was favored (case context: just one small lung metastasis, older age, significant comorbidities). The recommended timing of treatment (i.e. immediate or delayed treatment) was different between continents in 1/9 cases (11%, p = 0.012) and between years of experience in 5/7 cases (56%, all p &lt; 0.001); medical oncologists from Europe and with &lt; 5 years of experience preferred delayed treatment more often. Conclusions: This international survey based on case-vignettes indicated that immediate treatment was mostly preferred in asymptomatic patients with mPDAC. However, in one-third of cases, delayed treatment initiation was favored (e.g., due to patient selection and oncologists preference). The relation between timing of systemic treatment initiation and outcome in mPDAC is unknown and warrants further investigation.
Characterization of tumor antigen expression and myeloid immune profiles to inform the development of immune stimulating antibody conjugates (ISACs).
Authors: Lisa K. Blum, Jason Ptacek, Heidi LeBlanc, William G. Mallet, Bruce A. Hug, Michael N. Alonso, Edith A. Perez, David Dornan, Marcin Kowanetz
Journal: Journal of Clinical Oncology (2022)

2557 Background: Immuno-oncology (IO) has historically focused on T cell-driven effects, but a growing class of myeloid therapies are under investigation. This class includes immune-stimulating antibody conjugates (ISACs), which comprise a tumor-targeting antibody conjugated to an immune-stimulating payload. ISACs may require both tumor-associated antigens and tumor-resident myeloid cells for activity. As new IO strategies such as TLR-activating ISACs are developed, understanding the myeloid landscape is relevant for cancer biology and drug development. Methods: Tumor microarrays with formalin-fixed paraffin embedded sections of breast (BC), colorectal (CRC), gastric (GC), head and neck squamous cell (HNSCC), and non-small cell lung (NSCLC) cancers were analyzed by immunohistochemistry for tumor antigens (HER2, CEA, PD-L1), myeloid cell markers (CD68/CD163/CD11c/BDCA2), and CD8+ T cells. Results: Tumor infiltrating myeloid cells and CD8+ T cells varied across indications (Table). Low densities of intra-tumoral CD8+ T cells (&lt;100/mm 2 ) were observed in CRC, with higher CD8+ T cell counts observed in other cohorts. In contrast to T cells, substantial myeloid infiltrates were observed across tumor types. While MSI status was associated with higher CD8+ T cell infiltration in CRC, myeloid cells were abundant in both MSI and MSS samples. Monocyte-derived (mDC) and conventional DCs (cDC), which respond strongly to TLR activation, were present in all indications, with highest numbers observed in NSCLC. HER2+ BC samples had high infiltration of plasmacytoid DCs, a key TLR7-responsive population. PD-L1 expression on immune cells was associated with higher CD8+ T cell and myeloid cell numbers. In contrast to HER2 and PD-L1, CEA expression was independent of immune infiltration. Conclusions: Abundant myeloid infiltrates were observed across solid tumors, independent of T-cell infiltration. The presence of myeloid cells in multiple tumor types offers broadscale therapeutic targets for ISACs and other myeloid-directed therapies that can activate the innate immune system as a bridge to adaptive immunity.[Table: see text]